Technical guidelines for the production and acceptance of a European Reference Material

General principles

Every European Reference Material project must be executed in accordance with
internationally accepted guidelines such as ISO-Guides 30-35 (and more
particularly ISO Guide 34, specifying the general requirements for the
competence of reference material producers), WHO Guidelines (for clinical
reference materials), the ISO-Guide to the Expression of Uncertainty in
Measurement (GUM), etc.

Details of a finalised European Reference Material project are summarised in a
submission document, which specifies the selection of base material, technical
aspects of the production process of the candidate material and its subsequent
storage, homogeneity control, short- and long-term stability testing,
characterisation of the batch, long-term storage conditions, and planned
stability monitoring. This document is submitted to the ERM technical
committee for review and technical acceptance. Finally, the submission is
forwarded to the ERM panel for approval, and the material can be released for
sales.

European Reference Materials samples

European Reference Materials sample containers (bottles, vials, ampoules,
etc.) have to be tight and must contain not less than the stated amount of
material.

Samples must have appropriate homogeneity and stability for their intended use.

Whenever relevant (e.g., in case of clinical ERM-CRMs), the commutability of
the European Reference Material has to be assured.

Packaging must be appropriate for the purpose.

Labelling must be clear and of good quality.

Homogeneity testing

Between-bottle homogeneity must be examined. Previous experience might be
available demonstrating that a specific CRM can be prepared with negligible
heterogeneity (for instance some solutions). However, even in such cases
homogeneity testing is required to confirm the appropriate homogeneity of the
material.

Any possible between-bottle heterogeneity must be accounted for in the overall
estimated CRM uncertainty. This requirement applies even when no statistically
significant between-bottle variation is present. In this case the method
variation or the actual calculated between-bottle variation (whichever is
larger) should be included in the overall uncertainty.

Stability testing

Long-term stability must be positively demonstrated by appropriate statistical
extrapolation for the certified European Reference Material's shelf-life to be
within the certified uncertainty; the related uncertainty contribution shall
be part of the estimated CRM uncertainty.

Exceptions can be made, when instability of the material can be considered
negligible (element composition of steels or alloys). In such cases the
uncertainty contribution of long-term stability is set zero. In all other
cases this parameter is determined from regression analysis of the results of
the long-term stability study.

Whenever possible, stability studies should be carried out using isochronous
measurements.

Batch characterisation

When a quantity that is not method dependant is certified, batch
characterisation can be carried out

by a primary method of measurement, or

by laboratory inter-comparison, using, whenever possible, two or more
independent analytical methods.

When a method-dependant quantity is certified by a laboratory
inter-comparison, all laboratories must strictly comply with the imposed
standard operating procedure.

The methods used must:

be applied under metrologically valid conditions,

have been properly validated before use (see ISO/IEC 17025: 5.4.5)

have precision and accuracy compatible with the target uncertainty.

Each set of measurements must:

be traceable to the stated references, and

be accompanied by a GUM-compatible uncertainty statement whenever possible.

Participant laboratories must:

have the required competence for the execution of the task in the European
Reference Material project,

be able to achieve traceability to the required stated references,

be able to estimate its measurement uncertainty in accordance with GUM,

have in place a sufficient and appropriate quality assurance system.

Estimation of uncertainty of batch-characterisation:

Whenever possible, standard uncertainties of batch-characterisation (uchar
) by both primary methods of measurement or laboratory inter-comparisons have
to be based on the combination of detailed uncertainty budgets of the
contributing values.

If insufficient information is available for values based on laboratory
inter-comparisons, uchar can, in the absence of uncertainties
common to all participants (e.g., common standard), also be approximated by
the standard deviation of the mean of laboratory means.

be able to estimate its measurement uncertainty in accordance with GUM,

If such common uncertainties are present, they have to be added to the
uncertainty of the mean of laboratory means.

Establishment of a certificate

The project responsible of a European Reference Material project establishes a
draft certificate (possibly complemented by a certification report) in
accordance with ISO Guide 30, containing all information relevant to and
needed by the user.

Certified values must be traceable to stated references and be accompanied by
a GUM-compatible expanded uncertainty statement valid for the entire
shelf-life of the European Reference Material.

After approval by the European Reference Materials panel, the certificate and
report are made available, both on the European Reference Materials-web site
and in printed form, and the European Reference Material is put on sale.

Transfer of samples to final storage place

To avoid degradation after certification, all samples are best transported to
the location which offers the conditions designated for the final storage of
the European Reference Material before measurements are started.

Otherwise, they must be transported from door to door keeping them at all
times under such storage conditions for which it has been demonstrated that
there is no influence on the certified values.